Toward the clinical translation of safe intravenous long circulating ILNEs contrast agent for CT imaging.

X-ray computed tomography (CT) is crucial in precision medicine for diagnostic and therapeutic guidance. However, current small molecule CT contrast agents pose risks such as nephrotoxicity, short blood circulation time, limited scan durations, potential thyroid impact, and immune responses. These challenges necessitate the development of kidney-safe nanoparticle (NP)-based contrast agents (CAs). We developed safe intravenous blood pool NP-based CT CAs at a clinical-equivalent dose of 300 mgI/kg, suitable for vascular and hepatic imaging. Our iodinated lipid nanoemulsions (ILNEs) were optimized for shelf-life stability, osmolarity, and viscosity for excellent injectability. The ILNEs were designed to offer high contrast and were tested for minimal protein interaction, prolonged blood circulation, and hepatic clearance. studies, along with tests in mice and porcine models, were conducted to confirm safety, cytocompatibility, and absence of tissue damage. The ILNEs demonstrated high x-ray attenuation, improved contrast enhancement, extended stability, and batch-to-batch consistency. They exhibited minimal protein interaction, prolonged blood residency of about 4 h, and hepatic clearance within three days, avoiding nephrotoxicity. Blood and thyroid-stimulating hormone (TSH) analyses, along with kidney and liver function tests, confirmed the safety of ILNEs. Our ILNEs offer a promising alternative to current CT contrast agents, with improved safety and efficacy profiles. The results support further toxicity evaluations for clinical translation, highlighting the potential of ILNEs in vascular and hepatic imaging without the associated risks of nephrotoxicity.